[Role of kappa1 opioid receptors and cAMP in regulation of cardiac tolerance to ischemia and reperfusion].
The cardioprotective, inotropic, and antiarrhythmic effects of U-50.488, a selective agonist of kappa1 opioid receptors (kappa1 ORs), was studied using the model of 45-min total ischemia and 30-min reperfusion of isolated rat heart. Cardiac kappa1 ORs were stimulated by adding U-50.488 to the perfusing solution up to the final concentration of 0.1 or 1 micromol/l. The opioid had no influence on the incidence of reperfusion arrhythmias. The addition of 0.1 micromol/l U-50.488 reduced the reperfusion release of creatine phosphokinase (CPK) by half, which positively correlated with the decrease in the myocardial cAMP content (r = 0.89, p < 0.01). At the same time, the addition of U-50.488 in the higher concentration (1 micromol/l) had no effect on either cAMP level or CPK release. These results indicate that the cardioprotective effect of U-50.488 may be connected with the reduction of myocardial cAMP content. Activation of kappa1 ORs caused a decrease in both frequency and amplitude of myocardial contractions. The negative inotropic and chronotropic effect of U-50.488 was shown to be independent of changes in the myocardial cAMP content. A hypothesis is proposed that the absence of any cardioprotective effect of U-50.488 at the higher concentration (1 micromol/l) is accounted for by its interaction with unknown nonopioid receptors of cardiac myocytes.
Lasukova
T V
TV
Maslov
L N
LN
Platonov
A A
AA
Guzarova
N V
NV
Lishmanov
Iu B
IuB
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015424:Reperfusion
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D017473:Receptors, Opioid, kappa; C116587:kappa(1) opioid receptor; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000242:Cyclic AMP; D003402:Creatine Kinase